Disturbances of mood (affective disorders: cf, R. J. Baldessarini in Goodman and Gillman's The Pharmacological Basis of Therapeutics. A. G. Gilman, L. S. Goodman, T. W. Rall and F. Murad, Eds., Macmillan, New York, 1985, pp 412-432) are the most common psychiatric disorders in adults. It has been estimated that 18-23% of women and 8-11% of men in the United States experience at least one major depressive episode in their lifetimes. Unfortunately, there are major drawbacks to the use of currently available agents for treating affective disorders. For example, no antidepressant drug to date has proven to be superior to electroconvulsive shock therapy in the treatment of severe, suicidal depression. Other problems with the use of the various available drugs are delayed onset of activity, poor efficacy, anticholinergic effects at therapeutic doses, cardiotoxicity, convulsions and the danger of taking a fatal overdose. There also exists a large number of untreated individuals and treatment-resistant patients in need of effective therapy.
It is now recognized that depressive conditions may result from reduced amounts of certain biogenic amine neurotransmitters such as noradrenaline (NA), dopamine (DA) and serotonin (5-HT) in the central nervous system (CNS). Therapeutic agents can theoretically raise the synaptic levels of these biogenic amine neurotransmitters in the CNS by two principal mechanisms: by inhibition of the neuronal uptake of the biogenic amine neurotransmitters and by inhibition of the metabolic enzymes responsible for converting the biogenic amines to inactive metabolites, such as, for example, monoamine oxidase (MAO). Biogenic amine uptake inhibitors, including classical antidepressants such as imipramine, desipramine and amitriptyline, as well as newer non-classical agents such as fluoxetine (Prozac) are well known to be therapeutically useful in the treatment of affective disorders such as depression, and related CNS disorders. These clinically-effective agents exert their therapeutic effect through the inhibition of the uptake of biogenic amines into neuronal terminals in the CNS, cf: R. W. Fuller, in Antidepressants: Neurochemical, Behavioral and Clinical Perspectives, S. J. Enna, J. D. Malick, and E. Richelson, Eds, Raven Press, New York, 1981, pp 1-12; L. E. Hollister, Drugs 1981, 22:129; J. Schildkraut in Psychopharmacology: A Generation of Progress, A. M. Lipton, A. DiMascio and K. F. Killam, Eds, Raven Press, New York, 1978, pp 1223-1234; F. Sulser in Typical and Atypical Antidepressants:Molecular Mechanisms, E. Costa and G. Racagni, Eds., Raven Press, New York, 1982, pp 1-20; W. Kostowski, Trends Pharmacol. Sci. 1981, 2:314; J. Maj, Trends Pharmacol. Sci. 1981, 2:80; and C. Kaiser and P. E. Setler in Burger's Medicinal Chemistry, 4th ed., M. E. Wolff, Ed., Wiley, New York, 1979, Part III, pp 997-1067.
The novel compounds of the present invention are potent inhibitors of biogenic amine neuronal uptake. Other tetrahydrobenz[e]isoindolines and octahydrobenz[h]isoquinolines, which have distinctly different or no known utility, are disclosed by J. F. DeBernardis, et al., U.S. Pat. No. 4,618,683, issued Oct. 21, 1986; by J. G. Cannon, et al., J. Med. Chem., 1980, 23:502-505; and by W. Oppolozer, Tetrahedron Letters, 1974, 1001-4.